An Evidence-Based Medicine Approach to the Evaluation of the Role of Exogenous Risk Factors in Sporadic Amyotrophic Lateral Sclerosis

Abstract

An evidence-based medicine approach was applied to evaluate analytic studies of exogenous risk factors for amyotrophic lateral sclerosis (ALS) published since 1991. Classification systems for evaluating the literature and for drawing conclusions based on the class of available evidence were developed, modeled on those used by national societies. Considerations regarding the impact on the general public of confirming a role for putative risk factors were made explicit. There was evidence in support of smoking being a probable (‘more likely than not’) risk factor for ALS. Smoking has broad public health impact, no redeeming features, and is a modifiable risk factor. Evidence supported the conclusion that the following were probably not risk factors for ALS: trauma, physical activity, residence in rural areas and alcohol consumption. Evidence-based medicine methodology does not permit calculation of the magnitude of type I or type II errors in drawing these conclusions. New evidence may change these conclusions. Recommendations for future research include: draw on clinical trial methodology in designing future, confirmatory, case-control studies; consider utilizing cohort studies, recognizing the longer timelines for these to come to fruition; accord priority to investigating putative risk factors with greatest public health impact. Advances in study methodology may lead to development of finite research cycles for individual putative risk factors for sporadic ALS.

Redox Modifier Genes and Pathways in Amyotrophic Lateral Sclerosis

“…Oxidative damage is known to increase with age, and the main risk factors for ALS-those that are consistently identified in epidemiology studies-are increasing age, male gender, and smoking (5,10,38). Moreover, biochemical markers of oxidative injury are abnormally high in postmortem samples from ALS patients (126).…”

Case Series Investigation of Amyotrophic Lateral Sclerosis (ALS) Among Former Kelly Air Force Base Workers

“…At 10.6 males per female, the gender ratio was roughly 5 to 6 times greater than what is normally reported. 3 ' 4 ' 8 ' 11,13, 14, 17, 18 The predominantly male case series also differed from the U.S. adult male population in the prevalence of several medical conditions mainly associated with obesity and/or metabolic syndrome. Another noteworthy and rather unexpected finding was that 6.5% of the cases had been professional or semi-professional athletes.…”

“…-15, 17 Historically, males are slightly more affected, with male to female ratios reported at 1.5:1 to 2.0:1.' 34,[17][18][19] However, in recent years, the gender gap in ALS incidence rates has appeared to narrow for unknown reasons.8' 10,13,14 A robust association is seen between ALS and increasing age, with peak onset in the 55 to 75 age group.3, 10 ,15,16 As for race, evidence for higher ALS incidence rates in whites compared to non-whites is inconsistent. 15 , 16 Geographic differences, perhaps related to latitude, may correlate with any noted race/ethnicity differences.…”

“…Numerous environmental factors have been hypothesized and investigated as possible disease triggers, but these studies have found only weak associations, if any, between these exposures and ALS. 18 In May 2001, the ATSDR responded to a request from 2 8 th District Congressman Ciro Rodriguez of Texas to investigate the medical literature pertaining to Kelly AFB contaminants and their possible links with ALS. The ATSDR report, released in May 2002, included a focused literature review, a description of the epidemiology and clinical features of ALS, and an analysis of ALS death rates in Bexar County, TX from 1989-1998.2 Only those papers considering associations between ALS and environmental pollutants that might be present on or around the former Kelly AFB, such as heavy metals, dietary trace elements, agricultural/non-agricultural solvents and chemicals, specific types of occupational exposures, and radiation (both ionizing and non-ionizing), were included in the ATSDR review.…”

127th ENMC International Workshop: Implementation of a European Registry of ALS Naarden, The Netherlands, 8–10 October 2004

“…Biological plausibility: the association between the disease and exposure should be consistent with a recognized biologic mechanism. The lack of evidence in support of a cause-effect relationship between ALS and the reported exposures may be explained by the poor design of the published studies, most of which do not qualify for class I or class II studies based on suggested standard EBM criteria [31]. Regardless of the type of exposure, individual susceptibility may be implicated through concurrent clinical conditions (eg, osteoporosis or hyperparathyroidism) or simply through an altered genetic background; thus, ALS may be the consequence of a complex interaction between genetic and environmental factors.…”